The Poxyiridae family of DNA viruses includes the orthopoxviruses Variola (smallpox) and the emerging pathogen monkeypox. Naturally occurring smallpox was eradicated through concerted vaccination with the prototypical orthopoxvirus, vaccinia, and routine vaccination has since been discontinued1. The potential use of smallpox as a bioweapon, however, has heightened interest in developing countermeasures2. In addition, recent reports show an increase in human monkeypox cases in Africa over the last 30 years3, and the first report of human monkeypox in the Western Hemisphere occurred in 20034.
Orthopoxviruses replicate in the cytoplasm and encode macromolecular machinery for transcription, post-transcriptional mRNA processing, and DNA genome replication6. Gene expression proceeds in a classical cascade mechanism that is broadly categorized into early, intermediate, and late phases7. Viral replication occurs in perinuclear viral factories and a major mode of transmission of these predominantly intracellular viruses is to adjacent cells via trafficking to the cell membrane or upon infected cell rupture8. While these core viral functions are conserved across orthopoxviruses, host-range and virulence factors are divergent9 10. Variola is an obligate human pathogen with a mortality rate of 30-50% which caused an estimated 300-500 million deaths in the 20th century11. Monkeypox has a mortality rate of 1-10% and can transmit to humans zoonotically from animal reservoirs12.
Retroviruses are extremely successful pathogens affecting virtually all branches of life. These viruses are champions of persistence, and are maintained as proviral DNAs integrated into the genome of somatic cells and can even enter into the germ line. Infection can result in cell death, or in oncogenic transformation by insertional mutagenesis. Thus, there is tremendous evolutionary selective pressure to block or prevent retrovirus replication (D. Wolf and S. P. Goff, 2008, Ann. Rev. Gen., 42: 143-163).